肿瘤突变负荷（TMB）是跨癌种预测免疫检查点PD-L1抗体治疗反应的重要生物标志物。目前，TruSight Oncology 500（TSO500）常规化检测TMB已在全球使用。三星医学中心在2019年至2021年期间在真实世界临床实践中，1744名癌症患者接受了TSO500检测，其中426名接受了PD-L1抗体治疗。分析了TMB与PD-L1抗体治疗的临床结果之间的相关性。应用数字空间定位技术（DSP）调查了高TMB（TMB-H）患者（n=8）的肿瘤免疫环境对PD-L1抗体治疗的影响。TMB-H（每兆碱基对应的突变数量≥10）的发生率为14.7％（n=257）。在TMB-H患者中，最常见的癌症类型是结直肠癌（n=108，42.0％），其次是胃癌（n=49，19.1％）、膀胱癌（n=21，8.2％）、胆管癌（n=21，8.2％）、非小细胞肺癌（n=17，6.6％）、黑色素瘤（n=8，3.1％）、胆囊癌（n=7，2.7％）和其他（n=26，10.1％）。TMB-H患者中抗PD-L1治疗的响应率与TMB低（TMB-L; <10突变/Mb）患者相比，在胃癌（71.4％ vs. 25.8％）、胆囊癌（50.0％ vs. 12.5％）、头颈癌（50.0％ vs. 11.1％）和黑色素瘤（71.4％ vs. 50.7％）中显著增加。对于TMB≥16突变/Mb的患者进行的进一步分析显示，与TMB-L患者相比，抗PD-L1治疗后的生存时间更长（未达到与418天之间，p=0.03）。TMB≥16突变/Mb的受益在与微卫星状态和PD-L1表达谱相结合时更为显著。在TMB-H患者中，对PD-L1治疗有反应的患者的肿瘤区域内有大量新活跃的免疫细胞。与非响应组相比，响应组的自然杀伤细胞（p=0.04）、细胞毒性T细胞（p<0.01）、记忆T细胞（p<0.01）、初记忆T细胞（p<0.01）以及与T细胞增殖有关的蛋白质（p<0.01）增加。相反，无反应组中消耗性T细胞和M2巨噬细胞计数增加。通过TSO500检测总体TMB状态的发生率为14.7％。 在真实世界的临床实践中，通过目标测序检测得出的TMB-H似乎能够预测对PD-L1抗体治疗的反应，尤其是在肿瘤区域富含更高比例的免疫细胞的患者中。©作者及其雇主（们）2023年。CC BY-NC下允许重新使用。不能进行商业再利用。由BMJ出版。

Tumor mutation burden (TMB) is an important biomarker to predict response to anti-PD-L1 treatment across cancer types. TruSight Oncology 500 (TSO500) is currently used globally as a routine assay for TMB.Between 2019 and 2021, 1744 patients with cancer received TSO500 assay as part of a real-world clinical practice at the Samsung Medical Center, and 426 received anti-PD-(L)1 treatment. Correlations between TMB and clinical outcomes of anti-PD-(L)1 were analyzed. Digital spatial profiling (DSP) was used to investigate the tumor immune environment's influence on the treatment response to anti-PD-(L)1 in high TMB (TMB-H) patients (n=8).The incidence of TMB-H (≥10 mutations (mt)/megabase (Mb)) was 14.7% (n=257). Among TMB-H patients, the most common cancer type was colorectal cancer (n=108, 42.0%), followed by gastric cancer (GC; n=49, 19.1%), bladder cancer (n=21, 8.2%), cholangiocarcinoma (n=21, 8.2%), non-small cell lung cancer (n=17, 6.6%), melanoma (n=8, 3.1%), gallbladder cancer (GBC; n=7, 2.7%), and others (n=26, 10.1%). The response rate to anti-PD-(L)1 therapy was substantially higher in GC (71.4% vs 25.8%), GBC (50.0% vs 12.5%), head and neck cancer (50.0% vs 11.1%), and melanoma (71.4% vs 50.7%) among TMB-H patients when compared with low TMB (TMB-L) (<10 mt/Mb) patients with statistical significance. Additional analysis of patients with TMB ≥16 mt/Mb demonstrated prolonged survival after anti-PD-(L)1 therapy compared with patients with TMB-L (not reached vs 418 days, p=0.03). The benefit of TMB ≥16 mt/Mb was greater when combined with microsatellite status and PD-L1 expression profiles. Among the TMB-H patients, those who responded to anti-PD-L1 therapy had numerous active immune cells that infiltrated the tumor regions during the DSP analysis. Natural killer cells (p=0.04), cytotoxic T cells (p<0.01), memory T cells (p<0.01), naïve memory T cells (p<0.01), and proteins related to T-cell proliferation (p<0.01) were observed in a responder group compared with a non-responder group. In contrast, exhausted T-cell and M2 macrophage counts were increased in the non-responder group.The overall incidence of TMB status was analyzed by the TSO500 assay, and TMB-H was observed in 14.7% of the pan-cancer population. In a real-world setting, TMB-H identified by a target sequencing panel seemed to predict response to anti-PD-(L)1 therapy, especially in patients with a higher proportion of immune cells enriched in the tumor region.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.